Alcohol Dependence, Withdrawal, and Relapse

Howard C. Becker,
Ph.D.

HOWARD C. BECKER, PH.D., is a professor in the Departments
of Psychiatry and Neuroscience, Medical University of South Carolina & VA
Medical Center, Charleston, South Carolina.

Continued
excessive alcohol consumption can lead to the development of dependence that is
associated with a withdrawal syndrome when alcohol consumption is ceased or substantially
reduced. This syndrome comprises physical signs as well as psychological symptoms
that contribute to distress and psychological discomfort. For some people the
fear of withdrawal symptoms may help perpetuate alcohol abuse; moreover, the presence
of withdrawal symptoms may contribute to relapse after periods of abstinence.
Withdrawal and relapse have been studied in both humans and animal models of alcoholism.
Clinical studies demonstrated that alcohol-dependent people are more sensitive
to relapse-provoking cues and stimuli than nondependent people, and similar observations
have been made in animal models of alcohol dependence, withdrawal, and relapse.
One factor contributing to relapse is withdrawal-related anxiety, which likely
reflects adaptive changes in the brain in response to continued alcohol exposure.
These changes affect, for example, the body’s stress response system. The
relationship between withdrawal, stress, and relapse also has implications for
the treatment of alcoholic patients. Interestingly, animals with a history of
alcohol dependence are more sensitive to certain medications that impact relapse-like
behavior than animals without such a history, suggesting that it may be possible
to develop medications that specifically target excessive, uncontrollable alcohol
consumption. Key words: Alcoholism; alcohol dependence; alcohol and other
drug (AOD) effects and consequences; neuroadaptation; AOD withdrawal syndrome;
AOD dependence relapse; pharmacotherapy; human studies; animal studies

The development of alcohol dependence is a complex and dynamic process. Many neurobiological
and environmental factors influence motivation to drink (Grant 1995; Samson and
Hodge 1996; Vengeliene et al. 2008; Weiss 2005). At any given time, an individual’s
propensity to imbibe is thought to reflect a balance between alcohol’s positive
reinforcing (i.e., rewarding) effects, such as euphoria and reduction of anxiety
(i.e., anxiolysis), and the drug’s aversive effects, which typically are
associated with negative consequences of alcohol consumption (e.g., hangover or
withdrawal symptoms). Memories associated with these rewarding and aversive qualities
of alcohol, as well as learned associations between these internal states and
related environmental stimuli or contexts, influence both the initiation and regulation
of intake. These experiential factors, together with biological and environmental
influences and social forces, are central to the formation of expectations about
the consequences of alcohol use. These expectations, in turn, shape an individual’s
decision about engaging in drinking behavior.

The nature of and extent
to which these factors are operable in influencing decisions about drinking not
only vary from one individual to another but also depend on the stage of addiction—that
is, whether the drinker is at the stage of initial experience with alcohol, early
problem drinking, or later excessive consumption associated with dependence. Although
many people abuse alcohol without meeting the criteria for alcohol dependence,1
[1To be diagnosed with alcohol dependence according to the Diagnostic
and Statistical Manual of Mental Disorders, 4th Edition (DSM–IV) (American
Psychiatric Association 1994), an individual must meet at least four of the following
criteria: drinking more alcohol than intended, unsuccessful efforts to reduce
alcohol drinking, giving up other activities in favor of drinking alcohol, spending
a great deal of time obtaining and drinking alcohol, continuing to drink alcohol
in spite of adverse physical and social effects, and the development of alcohol
tolerance.] continued excessive alcohol consumption can lead to the development
of dependence. Neuroadaptive changes that result from continued alcohol use and
abuse (which manifest as tolerance and physiological dependence) are thought to
be crucial in the transition from controlled alcohol use to more frequent and
excessive, uncontrollable drinking (Koob and Le Moal 2008). Indeed, for some dependent
individuals, the fear that withdrawal symptoms might emerge if they attempt to
stop or significantly curtail drinking may prominently contribute to the perpetuation
of alcohol use and abuse.

This article will provide an overview of the
basic features of alcohol dependence and the associated withdrawal syndrome, emphasizing
those components of withdrawal that especially are thought to contribute to the
problem of relapse. It will present evidence from both clinical and experimental
studies that highlights long-lasting physiological and emotional changes which
are characteristic of dependence and have been postulated to play a key role in
persistent vulnerability to relapse. In particular, it will review animal models
of alcohol dependence and withdrawal, as well as models of self-administration,
that have helped researchers elucidate brain mechanisms underlying relapse and
excessive drinking associated with dependence.

Alcohol Withdrawal

When an alcohol-dependent individual abruptly terminates or substantially reduces
his or her alcohol consumption, a characteristic withdrawal syndrome ensues. In
general, alcohol acts to suppress central nervous system (CNS) activity, and,
as with other CNS depressants, withdrawal symptoms associated with cessation of
chronic alcohol use are opposite in nature to the effects of intoxication. Typical
clinical features of alcohol withdrawal include the following (Becker 2000; Hall
and Zador 1997; Saitz 1998):

Signs of heightened autonomic nervous
system2 [2The autonomic nervous system is that division
of the nervous system which regulates the functions of the internal organs and
controls essential and involuntary bodily functions, such as respiration, blood
pressure and heart rate, or digestion.] activation, such as rapid heartbeat (i.e.,
tachycardia), elevated blood pressure, excessive sweating (i.e., diaphoresis),
and shaking (i.e., tremor);

Excessive activity of the CNS (i.e., CNS hyperexcitability)
that may culminate in motor seizures; and

Hallucinations and delirium
tremens in the most severe form of withdrawal.

In addition to physical
signs of withdrawal, a constellation of symptoms contributing to a state of distress
and psychological discomfort constitute a significant component of the withdrawal
syndrome (Anton and Becker 1995; Roelofs 1985; Schuckit et al. 1998). These symptoms
include emotional changes such as irritability, agitation, anxiety, and dysphoria,
as well as sleep disturbances, a sense of inability to experience pleasure (i.e.,
anhedonia), and frequent complaints about “achiness,” which possibly
may reflect a reduced threshold for pain sensitivity. Many of these signs and
symptoms, including those that reflect a negative-affect state (e.g., anxiety,
distress, and anhedonia) also have been demonstrated in animal studies involving
various models of dependence (Becker 2000).

Although many physical signs
and symptoms of withdrawal typically abate within a few days, symptoms associated
with psychological distress and dysphoria may linger for protracted periods of
time (Anton and Becker 1995; De Soto et al. 1985; Martinotti et al. 2008). The
persistence of these symptoms (e.g., anxiety, negative affect, altered reward
set point manifesting as dysphoria and/or anhedonia) may constitute a significant
motivational factor that leads to relapse to heavy drinking.

Studying
Alcohol Relapse Behavior

Relapse may be defined as the resumption of alcohol
drinking following a prolonged period of abstinence. Clinically, vulnerability
to relapse commonly is associated with an intense craving or desire to drink.
Although a precise definition for craving remains elusive (Anton 1999; Koob 2000;
Littleton 2000), and there even is some debate about the role of craving in relapse
(Miller and Gold 1994; Rohsenow and Monti 1999; Tiffany and Carter 1998), there
is no question that relapse represents a prevalent and significant problem in
alcoholism. In fact, given the high rate of recidivism in alcoholism, relapse
clearly is a major impediment to treatment efforts. Consequently, substantial
research efforts have been directed at modeling relapse behavior, as well as elucidating
neural substrates and environmental circumstances that are associated with or
promote excessive drinking.

Events that potently trigger relapse drinking
fall into three general categories: exposure to small amounts of alcohol (i.e.,
alcohol-induced priming), exposure to alcohol-related (i.e., conditioned) cues
or environmental contexts, and stress. Clinical laboratory studies have found
that compared with control subjects, alcohol-dependent people are more sensitive
to the ability of these stimuli and events to elicit craving and negative affect,
which in turn presumably drives an increased desire to drink (Fox et al. 2007;
Sinha et al. 2008). The combination of these clinical laboratory procedures with
neuroimaging techniques has proven to be a powerful tool allowing investigators
to identify brain regions that are more strongly activated in alcohol-dependent
subjects than in control subjects when they are exposed to these stimuli/events
(George et al. 2001; Myrick et al. 2004; Wrase et al. 2002). Similar experimental
procedures have been employed to evaluate the ability of pharmacotherapeutics
to quell craving and temper the brain activation provoked by alcohol-related cues
in humans (Anton et al. 2004; George et al. 2008; Myrick et al. 2007, 2008; O’Malley
et al. 2002).

More detailed insight regarding mechanisms underlying fundamental
changes in brain function that occur as a consequence of dependence and which
relate to enduring relapse vulnerability have been gained through research in
animals. Several animal models have been used to study alcohol self-administration
behavior and the issue of relapse (for reviews, see Le and Shaham 2002; Sanchis-Segura
and Spanagel 2006; Weiss 2005). In one type of model, animals with a long history
of daily access to alcohol are abruptly denied access to the drug. When alcohol
is reintroduced after this period of “forced” (i.e., experimenter-induced)
abstinence, the animals exhibit a transient increase in alcohol consumption. This
alcohol deprivation effect has been demonstrated using both measures of voluntary
alcohol consumption and operant procedures3 [3In operant
procedures, animals must first perform a certain response (e.g., press a lever)
before they receive a stimulus (e.g., a small amount of alcohol). By modifying
the required response (e.g., increasing the number of lever presses required before
the alcohol is delivered) researchers can determine the motivational value of
the stimulus for the animal ] (Heyser et al. 1997; Sinclair 1979; Spanagel and
Holter 1999). Another model frequently used to study alcohol (and other drug)
relapse behavior involves operant reinstatement procedures (Shaham et al. 2003).
In this model, animals first are trained to respond for access to alcohol (i.e.,
to receive the reinforcement provided by alcohol). Then, the response-contingent
reinforcement is interrupted with extinction training—that is, even if the
animals perform the required response, they do not receive alcohol; as a result,
the animals eventually reduce or even completely stop responding. When the animals
then are exposed again to small alcohol doses, environmental stressors, or stimuli
previously associated with delivery of alcohol (i.e., conditioned cues), they
resume responding (to varying degrees)—as if “seeking” alcohol
reinforcement (Le et al. 1998, 2000; Weiss et al. 2001). This renewed alcohol-seeking
behavior becomes even more robust when several of these relevant stimuli are presented
in combination (Backstrom and Hyytia 2004; Liu and Weiss 2002b). Interestingly,
this reinstatement of alcohol responding occurs even though the animals still
do not receive alcohol reinforcement.

This experimental design can be
further modified by the use of discriminative contextual cues. This means that
certain contextual cues (e.g., a unique odor or testing environment) will indicate
to the animal that responding will pay off with delivery of alcohol reinforcement,
whereas a different contextual cue is used to signal that responding will not
result in access to alcohol. If the responding is extinguished in these animals
(i.e., they cease to respond because they receive neither the alcohol-related
cues nor alcohol), presentation of a discriminative cue that previously signaled
alcohol availability will reinstate alcohol-seeking behavior. This renewed alcohol-seeking
behavior can be observed even after a long period of time has elapsed since the
animals last were given an opportunity to self-administer alcohol, suggesting
that these contextual cues can serve as powerful triggers for relapse-like behavior
(Ciccocioppo et al. 2001; Katner and Weiss 1999; Katner et al. 1999). Additional
studies (Chaudhri et al. 2008; Zironi et al. 2006) found that reexposure of the
animals to the general environmental context in which they could self-administer
alcohol not only enhanced subsequent alcohol responding but also modulated the
ability of alcohol-conditioned cues to reinstate alcohol-seeking behavior.

Finally, and perhaps most importantly, animals used in all of these models generally
have demonstrated sensitivity to treatment with various medications that have
been shown to be clinically effective in preventing and/or retarding alcohol relapse
(Burattini et al. 2006; Heilig and Egli 2006; Le and Shaham 2002; Marinelli et
al. 2007b; Spanagel and Kiefer 2008). From a clinical standpoint, this
is important because it underscores the value of these models in identifying and
evaluating new treatment strategies that may be more effective in battling the
problem of relapse.

Alcohol Dependence, Withdrawal, and Relapse

As mentioned earlier, alcohol addiction is a complex and dynamic process (see
figure 1). Prolonged excessive alcohol consumption sets in motion a host of neuroadaptive
changes in the brain’s reward and stress systems (for reviews, see Hansson
et al. 2008; Heilig and Koob 2007; Koob and Le Moal 2008; Vengeliene et al. 2008).
The development of alcohol dependence is thought to reflect an allostatic state—that
is, a state in which the chronic presence of alcohol produces a constant challenge
to regulatory systems that attempt (but ultimately fail) to defend the normal
equilibrium of various internal processes (i.e., homeostatic set points). In the
dependent individual, this allostatic state is fueled by progressive dysregulation
of the brain’s reward and stress systems beyond their normal homeostatic
limits (Koob 2003; Koob and Le Moal 2001). These neuroadaptive changes associated
with dependence and withdrawal are postulated to impact the rewarding effects
of alcohol and, consequently, contribute to the transition from controlled alcohol
use to more excessive, uncontrollable drinking. Manifestations of these perturbations
in brain reward and stress systems also appear to mediate the myriad symptoms
of alcohol withdrawal, as well as underlie persistent vulnerability to relapse.

As noted above, clinical laboratory studies have shown that alcohol-dependent
people are more sensitive to relapse-provoking cues/stimuli compared with control
subjects. By definition, alcohol-dependent subjects also are heavier drinkers
and (too) often experience an insidious return to excessive levels of alcohol
consumption once a “slip” occurs after abstinence. Not surprisingly,
numerous rodent and primate models have been employed to examine the influence
of dependence on relapse. Early studies using these animal models generally yielded
equivocal findings, most likely because investigators used procedures that neither
sufficiently established alcohol’s positive reinforcing effects prior to
dependence induction nor optimized the development of alcohol’s negative
reinforcing capacity (i.e., the animals did not have an opportunity to associate
alcohol drinking with alleviation of withdrawal symptoms) (Meisch 1983; Meisch
and Stewart 1994).

More recent studies that have incorporated these procedural
considerations, however, have demonstrated increased alcohol responding and/or
drinking in dependent compared with nondependent mice (Becker and Lopez 2004;
Chu et al. 2007; Dhaher et al. 2008; Finn et al. 2007; Lopez and Becker 2005)
and rats (O’Dell et al. 2004; Rimondini et al. 2003; Roberts et al. 2000;
Sommer et al. 2008; Valdez et al. 2002). Moreover, in some studies, the enhanced
alcohol consumption in dependent animals during withdrawal produced blood and
brain alcohol levels that nearly reached levels attained during the initial chronic
alcohol exposure which had produced the dependent state (Griffin et al. 2008;
Roberts et al. 2000). Also, consistent with the findings of clinical studies,
animals with a history of alcohol dependence exhibited exaggerated sensitivity
to alcohol-related cues and various stressors that lead to enhanced alcohol-seeking
behavior (Gehlert et al. 2007; Liu and Weiss 2002b; Sommer et al. 2008).
In many instances, these effects were observed long after the animals had experienced
chronic alcohol exposure (Lopez and Becker 2005; Rimondini et al. 2003; Valdez
et al. 2002). Finally, experience with repeated cycles of chronic alcohol exposure
and withdrawal not only led to an exacerbation of the physiological symptoms of
withdrawal but also to enhanced susceptibility to relapse (for more information
on this issue, see the sidebar, “Repeated Alcohol Withdrawals: Sensitization
and Implications for Relapse”). Thus, a growing body of evidence indicates
that alcohol dependence and withdrawal experiences significantly contribute to
enhanced relapse vulnerability as well as favor sustained high levels of alcohol
drinking once a “slip” occurs.

Figure
1 Schematic illustration of how problem drinking can lead to the development
of dependence, repeated withdrawal experiences, and enhanced vulnerability to
relapse. Alcohol dependence is characterized by fundamental changes in the brain’s
reward and stress systems that manifest as withdrawal symptoms when alcohol consumption
is stopped or substantially reduced. These changes also are purported to fuel
motivation to reengage in excessive drinking behavior. Repeated bouts of heavy
drinking interspersed with attempts at abstinence (i.e., withdrawal) may result
in sensitization of withdrawal symptoms, especially symptoms that contribute to
a negative emotional state. This, in turn, can lead to enhanced vulnerability
to relapse as well as favor perpetuation of excessive drinking.

Role of Withdrawal-Related Stress and Anxiety in Relapse

As previously noted, increased anxiety represents a significant component of the
alcohol withdrawal syndrome. Importantly, this negative-affect state may contribute
to increased risk for relapse as well as perpetuate continued use and abuse of
alcohol (Becker 1999; Driessen et al. 2001; Koob 2003; Roelofs 1985). Indeed,
both preclinical and clinical studies suggest a link between anxiety and propensity
to self-administer alcohol (Henniger et al. 2002; Spanagel et al. 1995; Willinger
et al. 2002).

Various experimental procedures have been used to demonstrate
increased behavioral anxiety in animal models of alcohol dependence and withdrawal
(Becker 2000; Kliethermes 2005). Many of these models involve procedures that
exploit the natural tendency of rodents to avoid environments (e.g., bright open
spaces) that may be considered dangerous or threatening, thereby eliciting an
internal state of fear or anxiety. Other models assess an animal’s propensity
to engage in social interaction with another (unfamiliar) animal of the same species
(Overstreet et al. 2002) or response under conflict situations (Sommer et al.
2008). Finally, some models use operant discrimination procedures to train animals
to discern subjective (i.e., interoceptive) cues associated with an anxiety-inducing
(i.e., anxiogenic) state experienced during withdrawal (Gauvin et al. 1992; Lal
et al. 1988).

Alcohol withdrawal–related anxiety is thought to reflect
manifestations of numerous adaptive changes in the brain resulting from prolonged
alcohol exposure, most notably alterations in the stress systems active in the
brain and the body’s hormone (i.e., endocrine) circuits. The hormonal stress
response is mediated by a system known as the hypothalamic–pituitary–adrenocortical
(HPA) axis. Within this system, stress induces the release of the hormone corticotrophin-releasing
factor (CRF) from a brain area called the hypothalamus. CRF acts on the pituitary
gland located directly below the hypothalamus, where it initiates the production
of a molecule called proopiomelanocortin (POMC). This compound is processed further
into smaller molecules, such as β-endorphin and adrenocorticotropic hormone
(ACTH). ACTH is carried via the blood stream to the adrenal glands (which are
located atop the kidneys), where it induces the release of stress hormones (i.e.,
glucocorticoids) that then act on target cells and tissues throughout the body
(including the brain). The main glucocorticoid in humans and other primates is
cortisol; the main glucocorticoid in rodents is corticosterone.

It is well
known that alcohol activates the HPA axis, with the magnitude and response profile
influenced by a host of variables, including the individual’s specific genetic
makeup (i.e., genotype) and sex as well as the alcohol dose ingested (Rivier 2000;
Wand 2000). Both clinical and experimental studies have documented profound disturbances
in HPA axis function following chronic alcohol exposure and withdrawal. For example,
in humans and rodents, chronic alcohol consumption results in a general elevation
in blood corticosteroid levels, with a typical flattening of changes in corticosteroid
levels that normally is observed throughout the day (Kakihana and Moore 1976;
Rasmussen et al. 2000; Tabakoff et al. 1978; Wand and Dobs 1991). At the same
time, paradoxically, HPA response to subsequent stress challenge consistently
is dampened (i.e., blunted) (Errico et al. 1993; Lee et al. 2000). Whereas the
overall heightened HPA axis activation associated with withdrawal usually resolves
within a few days (Adinoff et al. 1991; Tabakoff et al. 1978; Willenbring et al.
1984), the blunted responsiveness of the HPA axis to subsequent challenges appears
to persist for a protracted period of time (Adinoff et al. 1990; Costa et al.
1996; Lovallo et al. 2000). In some cases, this may be accompanied by reduced
basal levels of circulating corticosteroids (Marchesi et al. 1997; Rasmussen et
al. 2000; Zorrilla et al. 2001).

Figure
2. Enhanced voluntary alcohol drinking in dependent mice produced brain
alcohol concentrations similar to those achieved during the chronic alcohol exposure
that initially rendered the animals dependent. Samples were collected from the
nucleus accumbens of alcohol-dependent mice that had undergone three cycles of
chronic intermittent alcohol vapor exposure (red symbols) and nondependent controls
(black symbols). Samples were taken before, during, and after the 2-hour drinking
session, when the mice had the opportunity to voluntarily drink alcohol (15 percent
vol/vol) or water. Alcohol intake during the drinking session was 3.04 ±
0.15 g/kg for dependent mice and 2.32 ± 0.28 g/kg for nondependent mice.
The red bar indicates the 2-hour drinking session. Horizontal lines and shaded
area represent brain alcohol levels (means ± SEM) measured in the dependent
mice during chronic intermittent alcohol exposure (28.4 ± 3.5 mM).

In addition
to these HPA axis–related effects, alcohol alters CRF activity independent
of the HPA axis (Heilig and Koob 2007; Koob and Le Moal 2001). CRF is a 41–amino
acid neuropeptide that is widely distributed throughout the mammalian brain and
plays a critical role not only in regulating HPA axis activity but also in orchestrating
other behavioral and physiological responses to stress. To exert these effects,
CRF interacts with two types of receptors called CRF1 and CRF2
receptors that are located in the membrane surrounding the target cells on which
CRF acts. Outside of the hypothalamus, CRF and its receptors are found in an extensive
network of interconnected neural structures that are intimately associated with
the brain’s reward and stress pathways, such as the amygdala, bed nucleus
of stria terminalis (BNST), and prefrontal cortex. Following chronic alcohol exposure,
increased CRF release, along with an increase in the number (i.e., upregulation)
of CRF1 receptors, can be observed, especially in these brain areas.
These variations represent an important neuroadaptive change (Heilig and Koob
2007; Koob and Le Moal 2001) that is thought to be key in the emergence of withdrawal-related
anxiety and dysphoria, both of which likely are intimately tied to alcohol drinking
and relapse (Becker 1999; Koob 2003). The contribution of CRF to withdrawal-related
anxiety is supported by findings that agents which interfere with the normal actions
of CRF (i.e., CRF antagonists) can reduce the anxiety if they are administered
into the blood (i.e., systemically) (Breese et al. 2005; Sommer et al. 2008) or
directly into the CNS—that is, either into the fluid-filled spaces of the
brain (i.e., brain ventricles) (Baldwin et al. 1991; Valdez et al. 2003) or into
the central nucleus of the amygdala (Rassnick et al. 1993). This effect appears
to be mediated by CRF1 receptors because CRF antagonists that selectively
block CRF1 receptors result in anxiety reduction (Overstreet et al.
2004). Conversely, activation of CRF2 receptors may attenuate withdrawal-related
anxiety (Valdez et al. 2004). Thus, chronic alcohol exposure and withdrawal experiences
can be viewed as potent stressors that disrupt the functional integrity of the
HPA axis and also act on the extrahypothalamic CRF systems. This perturbation
in the brain and hormonal (i.e., neuro­endocrine) stress axes may have significant
implications for motivation for alcohol self-administration behavior.

Although
the circumstances and manner in which stress influences drinking behavior are
complex and not fully understood, it generally is acknowledged that stressful
life events prominently influence alcohol drinking and, in particular, may trigger
relapse (Brady and Sonne 1999; Sillaber and Henniger 2004; Sinha 2001; Weiss 2005).
Activation of the HPA axis and CRF-related brain stress circuitry resulting from
alcohol dependence likely contributes to amplified motivation to drink. For example,
animal studies have indicated that elevation of corticosteroid hormone levels
may enhance the propensity to drink through an interaction with the brain’s
main reward circuitry (i.e., mesocorticolimbic dopamine system) (Fahlke et al.
1996; Piazza and Le Moal 1997). A CRF antagonist that acts on both the CRF1
and CRF2 receptors (i.e., a nonselective peptide CRF antagonist) called
D-Phe-CRF12–42 reduced excessive drinking in dependent animals
when administered into the brain ventricles (Finn et al. 2007; Valdez et al. 2002)
or the central nucleus of the amygdala (Funk et al. 2006). Similarly, systemic
administration of antagonists that selectively act at the CRF1 receptor
also reduced upregulated drinking in dependent mice (Chu et al. 2007) and rats
(Funk et al. 2007; Gehlert et al. 2007).

Taken together, a substantial body of
evidence suggests that changes in CRF function within the brain and neuroendocrine
systems may influence motivation to resume alcohol self-administration either
directly and/or by mediating withdrawal-related anxiety and stress/dysphoria responses.

Sidebar

Repeated Alcohol Withdrawals

Sensitization
and Implications for Relapse

Given that alcoholism is a chronic relapsing
disease, many alcohol-dependent people invariably experience multiple bouts of
heavy drinking interspersed with periods of abstinence (i.e., withdrawal) of varying
duration. A convergent body of preclinical and clinical evidence has demonstrated
that a history of multiple detoxification/withdrawal experiences can result in
increased sensitivity to the withdrawal syndrome—a process known as “kindling”
(Becker and Littleton 1996; Becker 1998). For example, clinical studies have indicated
that a history of multiple detoxifications increases a person’s susceptibility
to more severe and medically complicated withdrawals in the future (e.g., Booth
and Blow 1993). Similarly, animal studies have demonstrated sensitization of electrographic
and behavioral measures of withdrawal seizure activity in mice following multiple
withdrawals compared with animals tested after a single withdrawal episode, even
if both groups of animals had been exposed to the same total amount of alcohol
(e.g., Becker and Hale 1993; Becker 1994; Veatch and Becker 2002, 2005).

Effects of Repeated Withdrawals on Emotional State and Stress Response

Most studies demonstrating this sensitization or “kindling” of alcohol
withdrawal primarily have focused on withdrawal-related excessive activity (i.e.,
hyperexcitability) of the central nervous system (CNS), as indicated by seizure
activity, because this parameter is relatively easy to observe in experimental
as well as clinical settings. More recently, however, researchers have been turning
their attention to the evaluation of changes in withdrawal symptoms that extend
beyond physical signs of withdrawal—that is, to those symptoms that fall
within the domain of psychological distress and dysphoria. This new focus is clinically
relevant because these symptoms (e.g., anxiety, negative affect, and altered reward
set point) may serve as potent instigators driving motivation to drink (Koob and
Le Moal 2008). Sensitization resulting from repeated withdrawal cycles and leading
to both more severe and more persistent symptoms therefore may constitute a significant
motivational factor that underlies increased risk for relapse (Becker 1998, 1999).

Furthermore, multiple withdrawal episodes provide repeated opportunities
for alcohol-dependent individuals to experience the negative reinforcing properties
of alcohol—that is, to associate alcohol consumption with the amelioration
of the negative consequences (e.g., withdrawal-related malaise) experienced during
attempts at abstinence. This association not only may serve as a powerful motivational
force that increases relapse vulnerability, but also favors escalation of alcohol
drinking and sustained levels of potentially harmful drinking. Thus, for many
dependent individuals, repeated withdrawal experiences may be especially relevant
in shaping motivation to seek alcohol and engage in excessive drinking behavior.

Support for the notion that repeated withdrawal experience progressively
intensifies withdrawal symptoms—which, in turn, impacts relapse vulnerability
and facilitates transition to uncontrollable drinking— primarily has come
from studies involving animal models. For example, animals with a history of chronic
alcohol exposure and repeated withdrawal experiences were shown to exhibit enhanced
withdrawal-related anxiety, as measured in a variety of behavioral tasks (Overstreet
et al. 2002, 2004; Sommer et al. 2008; Zhang et al. 2007). Moreover, such a history
enhanced the animals’ sensitivity to various stressors, as measured by the
stressors’ ability to activate the body’s stress response system (i.e.,
the hypothalamic–pituitary–adrenocortical [HPA] axis) (Becker 1999),
to produce anxiety-like behavior (Breese et al. 2005; Sommer et al. 2008), and
to trigger relapse-like behavior (Ciccocioppo et al. 2003). In all these cases,
increased activity of a signaling molecule called corticotropin-releasing factor
(CRF) was found to be a critical mediating factor. This finding lends support
to the idea that enhanced CRF activity represents a key neuroadaptive change that
is fueled by repeated withdrawal experience and which drives (at least in part)
the motivation to drink as well as amplifies responsiveness to stimuli/events
that provoke relapse (Heilig and Koob 2007; Koob and Le Moal 2008). (For more
information on the body’s stress response, including the HPA axis and CRF,
see the main article.)

Effects of Repeated
Withdrawals on Tolerance to Subjective Alcohol Effects and Alcohol Self-Administration

Researchers also have explored the effects of repeated withdrawal episodes on
the perceived subjective effects of alcohol. In animal studies using operant discrimination
procedures,1 [1In operant procedures, animals must first
perform a certain response (e.g., press a lever) before they receive a stimulus
(e.g., a small amount of alcohol). By modifying the required response (e.g., increasing
the number of lever presses required before the alcohol is delivered) researchers
can determine the motivational value of the stimulus for the animal.] the animals’
ability to detect (perceive) the subjective cues associated with alcohol intoxication
was diminished during withdrawal from chronic alcohol exposure, and this tolerance
effect was enhanced in mice that experienced multiple withdrawals during the course
of the chronic alcohol treatment (Becker and Baros 2006). Similarly, rats with
a history of repeated cycles of chronic alcohol exposure and withdrawal exhibited
long-lasting tolerance to the sedative/ hypnotic effects of alcohol (Rimondini
et al. 2008). Because changes in sensitivity as well as in the ability to detect
(perceive) subjective effects associated with alcohol intoxication may influence
decisions about drinking and, in particular, control over the amount consumed
during a given drinking occasion, these observations may be relevant to the problem
of relapse and excessive drinking. Indeed, clinical studies have indicated that
heavy drinkers exhibit a reduced capacity to detect (discriminate) internal cues
associated with alcohol intoxication (Hiltunen 1997; Jackson et al. 2001; Schuckit
and Klein 1991). Future studies will need to further explore the potential relationship
between increased tolerance to subjective effects of alcohol produced by repeated
withdrawal experience and enhanced propensity to imbibe.

Enhanced alcohol responding/ intake in dependent
animals occurred well beyond the period of acute withdrawal, and escalation of
alcohol self-administration was especially facilitated when dependence was induced
by delivering chronic alcohol in an intermittent rather than continuous fashion
(Lopez and Becker 2005; O’Dell et al. 2004). This latter finding suggests
that elevated alcohol self-administration does not merely result from long-term
alcohol exposure per se, but rather that repeated withdrawal experiences underlie
enhanced motivation for alcohol seeking/consumption. Additionally, the more cycles
of chronic alcohol exposure and withdrawal the animals were exposed to, the more
alcohol they ingested and the longer (i.e., for several weeks) the enhanced alcohol
intake was sustained following the final withdrawal episode compared with a separate
group of nondependent mice (Lopez and Becker 2005). This effect apparently was
specific to alcohol because repeated chronic alcohol exposure and withdrawal experience
did not produce alterations in the animals’ consumption of a sugar solution
(Becker and Lopez 2004). More detailed analyses of the pattern of alcohol consumption
revealed that dependent mice not only consumed more alcohol than nondependent
animals over the entire 2-hour period during which they had access to alcohol,
but that the rate of consumption was faster and progressively increased with successive
withdrawal test periods (Griffin et al. 2008).

In both mice and rats,
enhanced alcohol self-administration following repeated cycles of withdrawal was
associated with significantly higher resultant blood alcohol levels compared with
the levels achieved by nondependent animals (Becker and Lopez 2004; Roberts et
al. 2000). The greater (and faster) alcohol intake exhibited by dependent mice
also lead to significantly higher peak and more sustained alcohol concentrations
in the brain compared with the levels achieved after alcohol consumption in nondependent
animals (Griffin et al. 2008). Finally, greater voluntary alcohol consumption
in dependent mice produced brain alcohol concentrations that approximated those
levels experienced during the chronic intermittent alcohol exposure which had
rendered the animals dependent in the first place (see figure 2, main section).
Although it is tempting to speculate that dependent animals increase voluntary
alcohol drinking to attain blood and brain alcohol levels in a range consistent
with sustaining dependence, the extent to which resultant brain alcohol concentrations
help drive as well as perpetuate enhanced alcohol drinking in dependent animals
remains to be determined.

Effects of Repeated Withdrawals on Sensitivity
to Treatment

Some studies using animal models involving repeated withdrawals
have demonstrated altered sensitivity to treatment with medications designed to
quell sensitized withdrawal symptoms (Becker and Veatch 2002; Knapp et al. 2007;
Overstreet et al. 2007; Sommer et al. 2008; Veatch and Becker 2005). Moreover,
after receiving some of these medications, animals exhibited lower relapse vulnerability
and/or a reduced amount consumed once drinking was (re)-initiated (Ciccocioppo
et al. 2003; Finn et al. 2007; Funk et al. 2007; Walker and Koob 2008). These
findings have clear clinical relevance from a treatment perspective. Indeed, clinical
investigations similarly have reported that a history of multiple detoxifications
can impact responsiveness to and efficacy of various pharmacotherapeutics used
to manage alcohol dependence (Malcolm et al. 2000, 2002, 2007). Future studies
should focus on elucidating neural mechanisms underlying sensitization of symptoms
that contribute to a negative emotional state resulting from repeated withdrawal
experience. Such studies will undoubtedly reveal important insights that spark
development of new and more effective treatment strategies for relapse prevention
as well as aid people in controlling alcohol consumption that too often spirals
out of control to excessive levels.

Treatment Implications

Relapse represents
a major challenge to treatment efforts for people suffering from alcohol dependence.
To date, no therapeutic interventions can fully prevent relapse, sustain abstinence,
or temper the amount of drinking when a “slip” occurs. For some people,
loss of control over alcohol consumption can lead to alcohol dependence, rendering
them more susceptible to relapse as well as more vulnerable to engaging in drinking
behavior that often spirals out of control. Many of these people make numerous
attempts to curtail their alcohol use, only to find themselves reverting to patterns
of excessive consumption.

Significant advancements have been made in understanding
the neuro­biological underpinnings and environmental factors that influence
motivation to drink as well as the consequences of excessive alcohol use. Given
the diverse and widespread neuroadaptive changes that are set in motion as a consequence
of chronic alcohol exposure and withdrawal, it perhaps is not surprising that
no single pharmacological agent has proven to be fully successful in the treatment
of alcoholism. The challenge of choosing the most appropriate agent for the treatment
of alcoholism is compounded by the complexity and heterogeneity of this relapsing
disease as well as by the host of other variables (e.g., genotype, coexisting
disorders, treatment regimens, and compliance) that must be considered in the
context of treatment interventions (e.g., McLellan et al. 2000). Further, the
efficacy of treatment may depend on temporal factors, such as the stage of addiction
(e.g., whether the patient seeks treatment or not) as well as drinking pattern
(e.g., binge-like intake) (Anton et al. 2004), especially when both amount and
frequency of alcohol consumption is assessed to determine drinking behavior/phenotype
(Feunekes et al. 1999).

Nevertheless, numerous pharmacotherapies have
been employed to treat alcoholism, guided principally by advancing knowledge about
alcohol’s interactions with various components of the brain’s reward
and stress pathways (Heilig and Egli 2006; Litten et al. 2005; Spanagel and Kiefer
2008). To date, two medications targeting these brain systems—naltrexone
(Revia®) and acamprosate (Campral®)— have been approved by the Food
and Drug Administration (FDA) for treatment of alcoholism.6 [6A
third FDA-approved medication to treat alcohol dependence (disulfiram; Antabuse®)
targets alcohol metabolism.] The efficacy of naltrexone and acamprosate in treating
alcohol dependence and relapse is based on numerous clinical studies, although
support is not universal (Anton et al. 2006; Heilig and Egli 2006; Mann et al.
2008; Spanagel and Kiefer 2008). Naltrexone operates as an antagonist of certain
receptors (principally μ and δ receptors) for brain-signaling molecules
(i.e., neurotransmitters) called endogenous opiates that are involved in reward
systems, whereas acamprosate is thought to modulate signal transmission involving
another neurotransmitter called glutamate. It has been postulated that naltrexone
may blunt the rewarding effects of alcohol, whereas acamprosate may attenuate
adaptive changes during abstinence that favor relapse (Heilig and Egli 2006; Litten
et al. 2005).

As previously indicated, a variety of animal models have
been used to study the ability of these and other medications to reduce alcohol
consumption as well as prevent and/or retard relapse. Of particular interest are
studies demonstrating that animals with a history of dependence exhibit greater
sensitivity to some medications that impact alcohol relapse–like behavior
compared with animals without such a history (Ciccocioppo et al. 2003; Funk et
al. 2007; Gehlert et al. 2007; Liu and Weiss 2002a, b). These findings
raise the promising prospect that therapeutics may be developed which specifically
target excessive uncontrolled alcohol drinking without producing nonspecific effects
(i.e., without reducing certain behaviors in dependent as well as nondependent
subjects). Further advances in understanding the neurobiological factors that
bear on the complex problem of relapse will no doubt continue to enlighten and
facilitate discovery of new and more effective treatment strategies for controlling
excessive drinking associated with alcohol dependence.

Summary

A complex interplay among numerous biological and environmental factors governs
the motivational aspects of alcohol-seeking and drinking behavior throughout the
addiction process. Chronic excessive alcohol consumption can lead to the development
of dependence. When drinking is terminated, a characteristic withdrawal syndrome
ensues that includes potentially life-threatening physical symptoms as well as
a constellation of symptoms that contribute to psychological distress, anxiety,
and negative affect. Many withdrawal symptoms associated with this negative emotional
state persist for a long period of time and constitute a powerful motivational
force promoting the perpetuation of alcohol use/abuse as well as enhancing vulnerability
to relapse. Both clinical studies and basic research studies using animal models
have demonstrated that alcohol-related (conditioned) cues and contexts as well
as stressful stimuli and events can trigger relapse. Moreover, a history of dependence
appears to amplify responsiveness to such relapse-provoking stimuli and events.

Alcohol dependence is thought to represent a persistent dysfunctional
(i.e., allostatic) state in which the organism is ill-equipped to exert appropriate
behavioral control over alcohol drinking. Functional changes in brain and neuroendocrine
stress and reward systems as a result of chronic alcohol exposure and withdrawal
play a key role not only in altering the rewarding effects of alcohol, but also
in mediating the expression of various withdrawal symptoms that, in turn, impact
motivation to resume drinking. Although currently few treatments are available
for tackling this significant health problem and providing relief for those suffering
from the disease, there is hope. As new and exciting discoveries in neuroscience,
genetics, neuroimaging, and biological psychiatry/psychology continue to advance
understanding of the complexities of alcohol dependence, new insights will emerge
that point to novel targets for the next generation of therapeutics, which hopefully
will be more effective in preventing relapse and/or tempering alcohol intake in
people attempting to control their drinking problems.

Liu, X., and Weiss, F. Additive effect of stress and drug
cues on reinstatement of ethanol seeking: Exacerbation by history of dependence
and role of concurrent activation of corticotropin-releasing factor and opioid
mechanisms. Journal of Neuroscience 22:7856–7861, 2002b.
PMID:
12223538